Researchers Identify Immune System Defect Linked to Rare Skin Cancer
Bethesda, MD – A new study published November 11, 2025, reveals considerably reduced expression of Toll-like receptors 3 (TLR3) and 9 (TLR9) in the skin of individuals with epidermodysplasia verruciformis (EV), a rare genetic disorder predisposing sufferers to extensive warts and a high risk of skin cancer. The findings, stemming from a comparative skin analysis, offer potential new avenues for understanding and treating this debilitating condition.
EV, affecting an estimated 1 in 600,000 individuals globally, arises from mutations in the EVER1/TMC6 and EVER2/TMC8 genes, disrupting cell-mediated immunity. This latest research, conducted by scientists at the National Center for Biotechnology Information (NCBI), demonstrates a critical link between these genetic defects and impaired immune signaling within the skin. Specifically, the study found diminished TLR3 and TLR9 protein levels in EV-affected skin compared to healthy controls, suggesting a compromised ability to detect and respond to viral DNA-a key factor in controlling the human papillomavirus (HPV) infections that drive EV-related skin cancer advancement.
The study involved a detailed analysis of skin samples from individuals diagnosed with EV and healthy control subjects. Researchers utilized immunohistochemistry to quantify TLR3 and TLR9 expression levels. Results indicated a considerable decrease in both receptors within the epidermis of EV patients.TLR3 recognizes double-stranded RNA, frequently enough produced during viral replication, while TLR9 detects unmethylated CpG DNA motifs commonly found in viral genomes.
“The reduced expression of these TLRs likely contributes to the persistent HPV infection and subsequent malignant transformation observed in EV,” explained a researcher involved in the study. “Understanding this immune deficiency is crucial for developing targeted therapies to boost antiviral immunity and prevent cancer progression.”
Currently, treatment for EV focuses on managing symptoms, including wart removal through methods like cryotherapy, laser therapy, or topical medications.However, these approaches are often ineffective in preventing the development of skin cancers, especially squamous cell carcinoma. The NCBI teamS findings suggest that future therapeutic strategies could focus on restoring TLR3 and TLR9 function, perhaps through topical immunomodulators or gene therapy, to enhance the body’s natural defenses against HPV and reduce cancer risk. Further research is underway to investigate the precise mechanisms underlying TLR downregulation in EV and to explore the feasibility of these novel treatment approaches.